Reaction between anthranilic acids, salicylaldehydes and isocyanides in water: an efficient synthesis of 2-{[2-(alkylimino)-1-benzofuran-3-yliden]amino}benzoic acids

Article abstract of DOI:10.1016/j.tetlet.2009.05.017

A novel, one-pot and three-component reaction for the preparation of 2-{[2-(alkylimino)-1-benzofuran-3-yliden]amino}benzoic acids is described. Heating a mixture of an anthranilic acid, a salicylaldehyde, and an isocyanide in water affords the title compounds in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.05.017

Tetrahedron Letters 51 (2010) 27–29
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Tetrahedron Letters
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Reaction between anthranilic acids, salicylaldehydes and isocyanides
in water: an efficient synthesis of 2-{[2-(alkylimino)-1-
benzofuran-3-yliden]amino}benzoic acids
a
a
b
c
Mehdi Adib a, , Mohammad Mahdavi , Sharareh Bagherzadeh , Long-Guan Zhu , Mehdi Rahimi-Nasrabadi
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Chemistry Department, Zhejiang University, Hangzhou 310027, PR China
c Department of Chemistry, Imam Hossein University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, one-pot and three-component reaction for the preparation of 2-{[2-(alkylimino)-1-benzofuran-
3-yliden]amino}benzoic acids is described. Heating a mixture of an anthranilic acid, a salicylaldehyde,
and an isocyanide in water affords the title compounds in good to excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 February 2009
Revised 27 April 2009
Accepted 8 May 2009
Available online 13 May 2009
Keywords:
Anthranilic acids
Salicylaldehydes
Isocyanides
Multicomponent reactions
Synthesis in water
Multicomponent reactions (MCRs) are important for generating
high levels of diversity, as they allow more than two building
blocks to be combined in practical, time-saving one-pot operations,
giving rise to complex structures by simultaneous formation of two
or more bonds.1 MCRs contribute to the requirements of an envi-
ronmentally friendly process by reducing the number of synthetic
steps, energy consumption and waste production. MCRs, which
lead to interesting heterocyclic scaffolds, are particularly useful
for the construction of diverse chemical libraries of ‘drug-like’ mol-
ecules. Isocyanide-based MCRs are especially important in this
area.2,3
Through application of these MCRs, many different scaffolds are
now readily accessible.2,3,7
We were prompted to investigate whether the amine and the
carboxylic acid, if suitably contained within the same molecule,
could undergo the Ugi reaction more efficiently. We also added a
more nucleophilic oxygen (phenolic) to compete with the carbox-
ylate nucleophilic attack on the nitrilium ion intermediate in the
Ugi reaction. Thus anthranilic acids seemed to be a suitable choice
as the amine and carboxylic acid components, and salicylaldehydes
were selected as the carbonyl compound. This could allow varia-
tion in the skeleton of the U-4CR product, thus increasing the ver-
satility of the Ugi reaction and potentially leading to useful new
building blocks for the construction of chemical libraries.
Water is a desirable solvent for chemical reactions because it is
safe, non-toxic, environmentally friendly, readily available and
cheap compared to organic solvents.8 Since the pioneering studies
on Diels–Alder reactions by Breslow,9 there has been increasing
recognition that organic reactions can proceed well in aqueous
media and offer advantages over those occurring in organic
solvents.8
The high efficiency of isocyanides in MCRs is due to their pro-
nounced reactivity towards C(sp2 or sp) electrophilic centres.2–5
A prominent example is the Ugi four-component reaction (U-
4CR),2,3,6 which combines an amine, an aldehyde, an isocyanide
and a carboxylic acid to give an
a-acylamino amide 1. In the U-
4CR, equilibria between the four components are displaced by a fi-
nal irreversible Mumm-type rearrangement (Scheme 1). The key
C–C bond-forming step in this reaction involves nucleophilic addi-
tion of the carbon of an isocyanide to the imine/iminium formed
in situ by condensation of the amine and the aldehyde. This reac-
tion has been the subject of intensive research over recent decades.
As part of our ongoing program to develop new efficient meth-
ods for the preparation of biologically active heterocyclic com-
pounds from readily available building blocks,10 we report herein
a simple new method for the synthesis of 2-{[2-(alkylimino)-1-
benzofuran-3-yliden]amino}benzoic acids via a three-component
reaction. Thus heating a mixture of an anthranilic acid 2, a
* Corresponding author. Tel./fax: +98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.017

28
M. Adib et al. / Tetrahedron Letters 51 (2010) 27–29
_
R3CO2
H
N
R3CO2H
N
R4NC
+
+ R2NH2
R1CHO
R1
R1
R2
R2
R4
H
H
NH
R1
R1
R3CO2
N
N
irreversible
Mumm rearrangement
R2
R2
R1
R2
O
R3
N
N
+
_
N
R3CO2
R4
O
R4
1
Scheme 1. The Ugi four-component reaction mechanism.
salicylaldehyde 3 and an isocyanide 4 in water afforded the corre-
sponding 2-{[2-(alkylimino)-1-benzofuran-3-yliden]amino}ben-
zoic acids 5a–h in 77–93% yields (Scheme 2).
The isolated products 5 were characterised on the basis of IR, 1H
and 13C NMR spectroscopy, mass spectrometry and elemental anal-
ysis. The mass spectrum of 5c displayed a molecular ion (M+) peak
at m/z 378, which is 20 mass units (H2O + H2) lower than that of a
1:1:1 adduct of anthranilic acid, salicylaldehyde and 1,1,3,3-tetra-
methylbutyl isocyanide. The IR spectrum of 5c showed absorptions
at 2500–3100 (br) and 1660 cmÀ1 indicative of the acid functional-
ity. The 1H NMR spectrum of 5c exhibited three sharp singlets aris-
ing from the CMe3 (d 1.01 ppm), CMe2 (d 1.44 ppm) and methylene
(d 1.71 ppm) groups along with characteristic signals with appro-
priate chemical shifts and coupling constants for the eight H-atoms
of the two aromatic moieties. A fairly broad signal (d 8.55 ppm)
was observed for the carboxylic acid group. The 1H-decoupled
13C NMR spectrum of 5c showed 20 distinct resonances, in agree-
ment with the adduct structure.11 Single-crystal X-ray analysis of
5c conclusively confirmed its structure, and by analogy those of
compounds 5a,b,d–h. An ORTEP diagram of 5c is shown in
Figure 1.12
Figure 1. ORTEP representation of the molecular structure of 5c.
O
X
OH
X
CO2H
NH2
CHO
OH
_
water
+
N
R
+
+
C
N
100 ºC, 1.5 h
N
Y
R
O
Y
2
5
3
4
5
a
b
c
X
H
Y
H
H
H
R
% Yielda
cyclohexyl
tBu
90
93
H
H
1,1,3,3-tetramethylbutyl
89
87
85
83
80
77
d
e
H
OCH3
OCH3
H
cyclohexyl
tBu
H
f
Cl
Cl
Cl
cyclohexyl
tBu
tBu
g
h
H
OCH3
a Isolated yields
Scheme 2.

M. Adib et al. / Tetrahedron Letters 51 (2010) 27–29
2. Dömling, A. Chem. Rev. 2006, 106, 17–89.
29
O
N
3. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
4. Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971.
5. Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810–819.
6. Ugi, I.; Steinbrükner, C. Angew. Chem. 1960, 72, 267–268.
7. Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I. G.; Pirali, T. Angew.
Chem., Int. Ed. 2006, 45, 1099–1102; Ngouansavanh, T.; Zhu, J. P. Angew. Chem.,
Int. Ed. 2006, 45, 3495–3497; El Ka, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed.
2005, 44, 7961–7964; Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80;
Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471–1499; Zhu, J. P. Eur. J. Org.
Chem. 2003, 1133–1144; Janvier, P.; Sun, X. W.; Bienaymé, H.; Zhu, J. P. J. Am.
Chem. Soc. 2002, 124, 2560–2567; Fayol, A.; Zhu, J. P. Angew. Chem., Int. Ed.
2002, 41, 3633–3635.
X
O
H
X
CO2H
NH2
CHO
OH
+
_
C
+
R
N
Y
4
OH
Y
2
3
6
8. Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York, 1997;
Organic Synthesis in Water; Grieco, P. A., Ed.; Thomson Science: Glasgow,
Scotland, 1998; Li, C.-J. Chem. Rev. 2005, 105, 3095–3165.
9. Breslow, R. Acc. Chem. Res. 1991, 24, 159–164; Breslow, R. Acc. Chem. Res. 2004,
37, 471–478.
10. Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2008, 64, 10681–
10686; Adib, M.; Sayahi, M. H.; Mahernia, S.; Zhu, L. G. Tetrahedron Lett. 2008,
49, 945–947; Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 3180–
3182; Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 177–180; Adib,
M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2007, 63,
11135–11140; Adib, M.; Sheibani, E.; Mostofi, M.; Ghanbary, K.; Bijanzadeh, H.
R. Tetrahedron 2006, 62, 3435–3438.
O
O
O
X
X
_
X
OH
NH
OH
O
O
_
2 H
N
NH
N
N
+
N
R
R
R
O
OH
Y
Y
Y
5
7
8
11. Procedure for the preparation of 2-{[2-[(1,1,3,3-tetramethylbutyl)imino]-1-
benzofuran-3-yliden]amino}benzoic acid (5c):
A mixture of anthranilic acid
Scheme 3.
(0.137 g, 1 mmol), salicylaldehyde (0.122 g, 1 mmol) and 1,1,3,3-
tetramethylbutyl isocyanide (0.139 g, 1 mmol) in H2O (2 mL) was stirred at
100 °C for 1.5 h. The reaction mixture was cooled to room temperature, the
aqueous phase was extracted with CH2Cl2 (2 Â 5 mL) and dried over
magnesium sulfate. The solvent was evaporated and the residue was purified
by column chromatography using n-hexane–EtOAc (4:1) as eluent. The solvent
was removed and the product was obtained as colourless crystals, mp 148 °C
Mechanistically, first the anthranilic acid 2 condenses with the
aldehyde 3 to give an imine intermediate 6. Nucleophilic attack of
the isocyanide 4 on the imine, which is facilitated by protonation
with the adjacent carboxylic acid, leads to the formation of a nitri-
lium carboxylate intermediate 7, which subsequently undergoes
intramolecular attack by the adjacent phenol hydroxy group to
(dec.), yield 0.34 g, 89%. EI-MS, m/z (%): 378 (M+, 14). IR (KBr) ( max/cmÀ1):
m
2500–3100 (br) (OH), 1660 (C@O). Anal. Calcd for C23H26N2O3 (378.47): C,
72.99; H, 6.92; N, 7.40%. Found: C, 73.14; H, 6.78; N, 7.29%. 1H NMR
(250.1 MHz, CDCl3): d 1.01 [9H, s, C(CH3)3], 1.44 [6H, s, C(CH3)2], 1.71 (2H, s,
CH2), 6.64 (1H, d, J = 8.5 Hz, CH), 6.72 (1H, t, J = 7.3 Hz, CH), 7.02–7.10 (3H, m,
3CH), 7.25–7.35 (2H, m, 2CH), 8.05 (1H, dd, J = 1.3 Hz, J = 8.0 Hz, CH), 8.55 (1H,
br s, OH). 13C NMR (62.9 MHz, CDCl3): d 30.0 [C(CH3)2], 31.0 [C(CH3)3], 31.2
[C(CH3)3], 53.9 (CH2), 56.8 [C(CH3)2], 96.6 and 109.2 (2C), 109.8, 113.5, 115.7,
115.9, 120.0 and 122.2 (6CH), 127.3 (C), 131.8 and 135.1 (2CH), 148.8, 150.8
and 154.0 (3C), 173.3 (C@O). 2-{[2-(tert-Butylimino)-7-methoxy-1-benzofuran-
3-yliden]amino}benzoic acid (5e): Yield 0.30 g, 85%. Colourless crystals, mp
form
c-iminolactone intermediate 8. Finally, aerial oxidation of
this intermediate affords the product 5 (Scheme 3).
In summary, we have reported an efficient, one-pot, three-com-
ponent reaction between various anthranilic acids, salicylaldehydes
and isocyanides leading to 2-{[2-(alkylimino)-1-benzofuran-3-
yliden]amino}benzoic acids. Simple and readily available starting
materials, fairly short reaction times and good to excellent yields
of the products are advantages of this reaction.
164 °C (dec.). EI-MS, m/z (%): 352 (M+, 23). IR (KBr) ( max/cmÀ1): 2500–3150
m
(br) (OH), 1670 (C@O). Anal. Calcd for C20H20N2O4 (352.39): C, 68.17; H, 5.72;
N, 7.95%. Found: C, 68.31; H, 5.89; N, 7.80%. 1H NMR (250.1 MHz, CDCl3): d 1.39
[9H, s, C(CH3)3], 4.02 (3H, s, OCH3), 6.62–6.75 (4H, m, 4CH), 7.03 (1H, dd,
J = 7.8 Hz, J = 8.0 Hz, CH), 7.25–7.32 (1H, m, CH), 8.04 (1H, dd, J = 1.3 Hz,
J = 8.0 Hz, CH), 8.59 (1H, br s, OH). 13C NMR (62.9 MHz, CDCl3): d 30.5 [C(CH3)3],
53.8 [C(CH3)3], 56.3 (OCH3), 99.4 (C), 105.2 and 109.7 (2CH), 109.9 (C), 114.1,
116.5 and 123.4 (3CH), 129.5 (C), 132.4 and 135.6 (2CH), 138.2, 144.6, 151.2
and 154.3 (4C), 173.9 (C@O).
Acknowledgement
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/03).
12. Selected X-ray crystallographic data for compound 5c: C23H26N2O3, triclinic,
ꢀ
space group = P1, a = 9.4976(9) Å, b = 10.7431(10) Å, c = 11.9529(11) Å,
References and notes
a
= 67.067(3)°, b = 75.900(4)°,
c
= 72.271(3)°, V = 1058.95(17) Å3, T = 295(2) K,
Z = 2, Dcalcd = 1.187 g cmÀ3 = 0.079 mmÀ1, 2858 observed reflections, final
,
l
1. (a) Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun. 2002, 1682–1683; (b)
Mont, N.; Teixidó, J.; Borrell, J. I.; Kappe, C. O. Tetrahedron Lett. 2003, 44, 5385–
5387; (c) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 24,
4957–4980; (d) Cui, S. L.; Lin, X. F.; Wang, Y. G. J. Org. Chem. 2005, 70, 2866–
2869; (e) Huang, Y. J.; Yang, F. Y.; Zhu, C. J. J. Am. Chem. Soc. 2005, 127, 16386–
16387; (f) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
R1 = 0.052, wR2 = 0.149 and for all data R1 = 0.066, wR2 = 0.163. CCDC 717398
contains the supplementary crystallographic data for the structure reported in
this Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.